Istituto Superiore Di Sanità Research Articles

New psychoactive substances (NPS) are uncontrolled analogues of existing drugs or newly synthesized chemicals that exhibit psychopharmacological effects. Due to their diverse nature, composition, and increasing prevalence, they present significant challenges to the healthcare system and drug control policies. In response, healthcare system laboratories have developed analytical methods to detect NPS in biological samples. As a Regional Reference Centre, the Sicilian CRQ Laboratory (Regional Laboratory for Quality Control) developed and conducted an External Quality Assessment (EQA) study to assess, in collaboration with the Istituto Superiore di Sanità (ISS), the ability of different Italian laboratories to identify NPS and traditional drugs of abuse (DOA) in biological matrices.Two blood samples were spiked with substances from various drug classes, including synthetic cannabinoids, cathinones, synthetic opiates, and benzodiazepines, at concentrations ranging from 2 to 10 ng/mL. The blood samples were freeze-dried to ensure the stability of DOA and NPS. Twenty-two laboratories from the Italian healthcare system participated in this assessment. The information provided by the laboratories during the registration in an in-house platform included a general description of the laboratory, analytical technique, and the chosen panels of analytes. The same platform was employed to collect and statistically analyze the data and record laboratory feedback and comments.The evaluation of the results revealed that the participating laboratories employed three different techniques for analyzing the samples: GC-MS, LC-MS, and immunoenzymatic methods. Approximately 90 % of the laboratories utilized LC-MS techniques. Around 40 % of false negative results were obtained, with the worst results in the identification of 5-chloro AB PINACA. The results showed that laboratories that used LC-MS methods obtained better specificity and sensitivity compared to the laboratories using other techniques.The results obtained from this first assessment underscore the importance of external quality control schemes in identifying the most effective analytical techniques for detecting trace molecules in biological matrices. Since the judicial authorities have not yet established cut-off values for NPS, this EQA will enable participating laboratories to share their analytical methods and expertise, aiming to establish common criteria for NPS identification.

Abstract In 2016, WHO set the goal of elimination of Hepatitis C Virus (HCV) by 2030. Globally, about 58 million people have chronic HCV, which causes cirrhosis, hepatocellular carcinoma and death (around 300000 in 2019), representing a heavy burden for public health. In Italy, the incidence of HCV acute infection is around 0.11 per 100000, and the estimated number of non-diagnosed chronic infections is 280000. In order to reach WHO's goal, the Istituto Superiore di Sanità (ISS) and the Ministry of Health implemented a strategy based on the detection of silent chronic infections and their treatment with direct-acting antivirals (DAAs), which cure around 95% of HCV infections. Therefore, in 2022, Regione Piemonte started a screening program contacting all residents born between 1969 and 1989. The screening was performed with rapid blood tests (antibodies detection, sensibility and specificity ca. 99%), and in case of a positive result, a HCV-RNA test was offered to confirm chronic infection and the need for treatment with DAAs. The Local Health Authority TO3, invited 36120 out of 158017 eligible residents (temporary and permanent), in the period March 2022 - April 2023 with invitation letters or catch-up strategies on other occasions; 6000 rapid blood tests were used (16.6% of invited population), and 11 (0.19%) tested positive. The RNA test confirmed 5 (0.08%) results. All the positive subjects were referred to 2 hospitals for DAAs treatment. As demonstrated by ISS, HCV screening could represent an effective mean to meet WHO's goal of HCV elimination by 2030 and also allow us to reduce HCV's burden on public health; although, with the current low adhesion rate, these results may not be reachable. Therefore, it is necessary to implement health promotion campaigns, to involve more stakeholders, including social and healthcare associations, General Practitioners and policy-makers, as the entire population's health would benefit from a successful HCV elimination program. Key messages • HCV and viral hepatitis represent a heavy burden for public health, high costs for Health Systems and severely affect the quality of life of subjects with un-diagnosed chronic infections. • The availability of reliable, non-invasive, tests and of extremely effective treatments should move policy-makers to allocate more resources in the implementation of HCV eradication strategies.

To enhance its visibility, the Library of the Istituto Superiore di Sanità (ISS) along with the Scientific Communication Unit of the same institution delivered a set of informal online training sessions, or webinars, on their fields of expertise: information retrieval, publication, effective communication, and research evaluation, specifically addressed to internal users. The collaboration was extremely useful in terms of improved knowledge on skills available among the personnel of these two services. It increased trust in the competencies of internal staff and at the same time it contributed to develop awareness of the value of the services rendered. Skills to use available online resources for training were improved as well as ISS staff cohesion favouring the development of new collaborations.

The Library of the Istituto Superiore di Sanità (ISS), the Italian National Institute of Health, is the main library for public health and biomedical research in Italy and holds a small but valuable special collection of ancient books. Known as the Rare Book Collection, this fund consists of over 1200 scientific printed volumes published between the XVI and the XIX century. The purpose of this paper is to illustrate the challenges and the process undertaken by the Library to share and digitalize this Collection.

In compliance with the European Council Decision 2005/387/JHA, the Italian AntiDrug Policies Department designated the National Center for Addiction and Doping of the Istituto Superiore di Sanità (ISS) to organize and manage the National Early Warning System (NEWS) on New Psychoactive Substances (NPS) to promote a rapid exchange of information on NPS within Italy and between Italy and the EU. The analytical pharmacotoxicology Unit of the Center supports NEWS with screening and confirmation of NPS presence in conventional and non-conventional biological matrices from acute and fatal intoxication cases. Furthermore, yearly, pure standards of new NPS are tested and provided to Laboratories from collaborative centres and proficiency testing on NPS in oral fluid and hair are organized. Different analytical technologies, including high-sensitivity gas chromatography-mass spectrometry (GC-MS) and tandem mass spectrometry (GC-MS-MS), liquid chromatography-tandem mass spctrometry (LC-MS-MS) and ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) are used for a screening and confirmation analysis of classic drugs, prescription medicines and new psychoactive substances in and their metabolites in blood, plasma, urine, hair and oral fluid from intoxication cases and clinical trials. Sample preparation involves both liquid-liquid or solid phase extraction. Dilute and shoot methodology is also applied. During 2021 and first months of 2022, around 80 different psychoactive substances, including new synthetic opioids and/or metabolites were identified in urine from 296 spanish patients with a history of opioid use disorder; 12 classic drugs and NPS were detected in hair from 300 mexican pregnant women; cocaine, THC, heroin, methadone, ketamine and mephedrone and metabolites were determined in urine from 76 italian prisoners; JWH-122 and JWH-210, UR-144 were quantified in oral fluid from consumers and finally some cases of intoxications with fentanyl, norfentanyl and analogs were also disclosed. Furthermore, two exercises of Proficiency testing for NPS in oral fluid and hair were organized. Samples from both matrices were prepared in cooperation with Comedical (Trento, Italy). For the 2021 round classic drugs together with 5-fluoro CUMYL-PeGACLONE, 5-fluoro MDMB-PICA, AB-FUBINACA,5F-ADB, Ethylone, Euthylone, Furanylfentanyl, Ocfentanyl, Isobutyryl fentanyl, Fentanyl and Isotonitazene were included. For the 2022 round, classic drugs plus 5-MMPA, Methoxpropamine, Brorphine, Butonitazene, Etodesnitazene, Flunitazene, 4-fluoro MDMB-BUTICA, 5-fluoro CUMYL—PICA, 5-fluoro EDMB-PICA, 3-Methylmethcathinone, ADB-4en-PINACA, MDMB-4en-PICA were comprises. About 20 different pharmacotoxicological national laboratories participated in the exercised with very variable quali-quantitative results. Although the NPS phenomenon is not uniform, it is well known as a global problem, concerning all the region of the world. Due to the mutating nature of the phenomenon, we believe that investments in toxicological and forensic analytical data sources are strongly needed. Differently from the past when psychotropic drugs occupied the fingers of two hands, in the 21th century, more than 1000 NPS have been identified. Not all of them found the same diffusion in the illicit market, but many of them are temporary adulterant of substitute of controlled compounds or finally fake drugs. The values of accurate and immediately available toxicological and forensic data are crucial to the implementation of national and international early warning system on NPS. Indeed, the drug related severe intoxications and fatalities are seldom associated with the consumption of one substance alone. Drug consumption patterns are often characterized by polyconsumption of both classical drugs and NPS and laboratories supporting emergency rooms, forensic toxicologies and police forces must be enabled to identify the substance/s causing the acute or chronic intoxication or a fatality.

Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes, and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the last years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato (AISF), the Società Italiana di Diabetologia (SID) and the Società Italiana dell'Obesità (SIO) reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS). Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources. Level of evidence: Level of evidence of recommendations for each PICO question were reported according to available evidence.

This report illustrates the design and results of an activity of surveillance proposed by the National Centre for Innovative Technologies in Public Health and the National Centre for Rare Diseases of the Istituto Superiore di Sanità with the aim of monitoring the state-of-use of technologies by people with frailty, disabilities, and rare diseases. The results of the surveillance activity reported in this report are as follows: (a) An international Webinar; (b) A Full report published by the Istituto Superiore di Sanità (ISS); (c) an electronic survey tool, for periodic monitoring; (d) an initial summary of the survey (15 September–30 November 2020), giving an overall picture relating to the state-of-use of technologies by the interviewed; (e) an understanding of the needs that emerged, causing reflection on the current state-of-the-art and offering important stimuli for all the stakeholders involved.

Data from the Istituto Superiore di Sanità (ISS) emphasized by the media indicate that COVID-19 vaccination reduces related infections, hospitalizations and deaths. However, a comparison showed significantly more hospitalizations and intensive care unit accesses in the corresponding months and days in 2021 versus 2020and no significant differences in deaths. The combination of non-alternative hypotheses may help explain the discrepancy between the results in the entire population and the vaccination's success claimed by the ISS in reducing infections, serious cases and deaths: a bias: counting as unvaccinated also "those vaccinated with 1 dose in the two weeks following the inoculation", and as incompletely vaccinated also "those vaccinated with 2 doses within two weeks of the 2nd inoculation".a systematic error: counting as unvaccinated also "vaccinated with 1 dose in the two weeks following the inoculation", and as incompletely vaccinated also "vaccinated with 2 doses within two weeks of the 2nd inoculation". Many reports show an increase in COVID-19 cases in these time-windows, and related data should be separated levels of protective effectiveness in vaccinated people, often considered stable, actually show signs of progressive reduction over time, which could contribute to reducing the overall population resultunvaccinated people show more severe disease than in 2020, supporting also in humans the theory of imperfect vaccines, which offer less resistance to the entry of germs than the resistance later encountered inside the human body. This favors the selection of more resistant and virulent mutants, that can be spread by vaccinated people. This damages first the unvaccinated people, but ultimately the whole community. An open scientific debate is needed to discuss these hypotheses, following the available evidence (as well as to discuss the inconsistent theory of unvaccinated young people as reservoirs of viruses/mutants), to assess the long-term and community impact of different vaccination strategies.

The rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emergency involved Italy as the first European country. Meanwhile, China was the only other country to experience the emergency scenario, implementing public health recommendations and raising concerns about the mental health of the population. The Italian National Institute of Health [Istituto Superiore di Sanità (ISS)] reviewed relevant scientific literature in mental health to evaluate the best clinical practices and established the collaboration with the WHO, World Psychiatry Association, and China to support the public health system in a phase of acute emergency. This process permitted the definition of organizational and practical-operational Italian guidelines for the protection of the well-being of healthcare workers. These guidelines have been extensively disseminated within the Italian territory for maximum stakeholder utilization.

Background and aimsAim of the present study is to determine the role of obesity as a risk factor for COronaVirus Disease-19 (COVID-19) hospitalization. Methods and resultsThis observational study was performed using Istituto Superiore di Sanità (ISS) Tuscany COVID-19 database by the Agenzia Regionale Sanità (ARS), including all COVID-19 cases registered until April 30th, 2020, with reported information on chronic diseases. The principal outcome was hospitalization. An age and gender-adjusted logistic regression model was used to assess the association of clinical and demographic characteristics with hospitalization. Further multivariate models were applied. Of 4481 included subjects (36.9% aged over 70 years), 1907 (42.6%) were admitted to hospital. Obesity was associated with hospitalization after adjusting for age and gender. The association of obesity with hospitalization retained statistical significance in a fully adjusted model, including possible confounders (OR: 2.99 [IC 95% 2.04–4.37]). The effect of obesity was more evident in younger (<70 years) than in older (≥70 years) subjects. ConclusionsThe present data confirm that obesity is associated with an increased risk of hospitalization in patients with COVID-19. Interestingly, the association of obesity with hospitalization was greater in younger (<70 years) patients.

IssuePreparedness can be considered the Achilles heel in Western Coutries to adequately fight Sars-CoV-2 pandemy. The Istituto Superiore di Sanità (ISS) has been challenged to give rapid technical and scientific advices to the State and Regions on a huge variety of Sars-CoV-2 aspects related to public health.Description of the problemRapid and timely accumulation of knowledge and empirical evidence is critical for policymakers and emergency managers to maximally inform their decisions through scientific evidence and to better guide and mobilise the expertise of academics and general practitioners towards effective solutions.ResultsAn ad hoc “Scientific Literature working group” at ISS in the period 23/03 - 31/05 screened a total of 4,568 pre-prints and 15,590 peer reviewed papers extracted from PubMed, arXiv.org, medRxiv and bioRxiv, which gave rise to the following deliverables: a) a daily pre-prints alert selection delivered to ISS President for the routine national Scientific Technical Committee meetings on Sars-CoV-2 chaired by Italian Civil Protection (still ongoing), and, b) a weekly open access issue of Covid Contents publications (8 volumes, https://www.iss.it/en/covid-contents), as summary of most interesting peer-reviewed papers for public health professions.LessonsThe needed cross-cutting approach is leading to: interdisciplinarity enhancement within the ISS; coverage of broad expertise areas and interest of health care providers; cross-linkage between the different aspects/disciplines involved in this pandemic and share of experiences.Key messages Committed Institutions have the responsibility to support practitioners and decision makers to understand relevant aspects of medical, physical, occupational and public safety, in case of emergency.The Silos culture has to be overcome. There is nothing more powerful in any Institution than having all researchers rowing fiercely in the same direction.

Abstract Background PASSI d'Argento (PdA) is an Italian population-based surveillance system, coordinated by the Istituto Superiore di Sanità (ISS) and carried out by the Local Health Units (LHUs). PdA monitors wide-ranged health related-behaviours in the elderly (65+) living in Italy as per the three pillars of the “Active Healthy Ageing” framework: Health, Participation, Security. Methods The PdA sample is randomly selected from the LHU lists, stratified by sex and age. 22,811 records have been collected in 2016-2017 on a representative sample of residents aged over65, not being hospitalised, in long-term care, in a nursing home or prison. Results 3,019 respondents resulted cancer-diagnosed elderly (CDE) reporting cancer diagnosis or confirmation, leukaemia and lymphomas included (annual average prevalence of 12.8%, Confidence Intervals 95%: 12.1-13.4%; one million and 729 thousand people). CDE refer: poorer health conditions (22%) than Chronic Elderly Patients (CEP; 18%) and Healthy Elderly (HE; 5%), sight impairment (12%), hearing loss (15%) and chewing problems (14%). CDE (10%) and CEP (11%) are more prone to fall than HE do (6%). Disability accounts for 21% in CDE and CEP vs. 12% in HE. A multivariate analysis confirms a compromised psychophysical health profile in CDE vs. HE, and vs. CEP. CDE behave still unhealthily, are insufficiently advised by health professionals, do not comply with the seasonal flu vaccination [Health]. CDE face increased risk for isolation or cognitive decline: they experience lower social connectedness (17%) than CEP (20%) and HE (28%) [Participation], and perceive higher neighbourhood insecurity (19%) than how CEP (17%) and HE (13%) do [Security]. Conclusions PdA data on the poor biopsychosocial health profile of CDE highlight to what extent healthy behaviours and prevention can ameliorate their quality of life PdA calls for global action strategies in Italy, which aim at taking complete charge of CDE and also CEP. Key messages In Italy, elderly cancer survivors show poor biopsychosocial health profile and overall quality of life. By modifying behaviours, elderly suffering from any cancer or chronic disease can age healthily.

Background: This systematic review summarizes the current knowledge on the superimposition of three-dimensional (3D) diagnostic records to realize an orthodontic virtual patient. The aim of this study is to analyze the accuracy of the state-of-the-art digital workflow. Methods: The research was carried out by an electronic and manual query effectuated from ISS (Istituto Superiore di Sanità in Rome) on three different databases (MEDLINE, Cochrane Library and ISI WEB OF SCIENCE) up to 31st January 2020. The search focused on studies that superimposed at least two different 3D records to build up a 3D virtual patient—information about the devices used to acquire 3D data, the software used to match data and the superimposition method applied have been summarized. Results: 1374 titles were retrieved from the electronic search. After title-abstract screening, 65 studies were selected. After full-text analysis, 21 studies were included in the review. Different 3D datasets were used: facial skeleton (FS), extraoral soft tissues (ST) and dentition (DENT). The information provided by the 3D data was superimposed in four different combinations: FS + DENT (13 papers), FS + ST (5 papers), ST + DENT (2 papers) and all the types (FS + ST + DENT) (1 paper). Conclusions: The surface-based method was most frequently used for 3D objects superimposition (11 papers), followed by the point-based method (6 papers), with or without fiducial markers, and the voxel-based method (1 paper). Most of the papers analyzed the accuracy of the superimposition procedure (15 papers), while the remaining were proof-of-principles (10 papers) or compared different methods (3 papers). Further studies should focus on the definition of a gold standard. The patient is going to have a huge advantage from complete digital planning when more information about the spatial relationship of anatomical structures are needed: ectopic, impacted and supernumerary teeth, root resorption and angulations, cleft lip and palate (CL/P), alveolar boundary conditions, periodontally compromised patients, temporary anchorage devices (TADs), maxillary transverse deficiency, airway analyses, obstructive sleep apnea (OSAS), TMJ disorders and orthognathic and cranio-facial surgery.

The Apulian Poison Centre (PC) of Foggia, Italy, annually manages numerous consultations concerning certain or suspected poisonings from pesticides, starting at the same time a careful activity related to the risk assessment phase. The management of the exposure to pesticides and to other chemicals, and the alerting of the “National center for chemicals, cosmetics and consumer protection” at the Istituto Superiore di Sanità (ISS), actively contributes to the improvement of products quality and safety. Thus, leading to a reduction in the number of intoxications - and therefore of the accesses to the emergency services - allows greater protection for workers, bystanders, residents and consumers. The reported case of methomyl poisoning has been of fundamental importance both from the medical point of view and for the management of the intoxicated patient, both for the risk assessment actions, and for cooperation with the competent authorities, generating discussion points on the regulations in force between PCs and National Competent Authority. It follows that the feedback of intoxication in an emergency can lead to improvements in the management and risk mitigation measures in order to reach a greater protection of human, animal, and environmental health. In addition, the regulatory feedback deriving from these reports is an input to the increase product quality improvement (mixtures, labels, packaging, and risk communication) leading to a greater protection of potential exposed subjects. The importance of creating an information and management network that allows the optimization of the flow of information deriving from PCs arises. The actions taken are therefore described, both relating to the management of the emergency, and relating to the subsequent information flow and to the measures for containing the consequent risks.

Between the end of the second and the beginning of the following century BC, the Greek philosopher Plutarch wrote “The parallel lives”, a series of twin biographies, each of which comparing a Greek and Roman prominent figure as for life events, vices and virtues. Now that our world is facing SARS-CoV-2 pandemics with its relevant country-specific timing and evolution pattern characteristics, we feel like repeating Plutarch’s parallelism experiment by analyzing factors eventually influencing its expression in different and far afield countries and by trying a head-to-head comparison between two main Italian regions. The history of COVID-19 pandemics is contributed to by a series of events occurring between the end of 2019 and the beginning of 2020 caused by SARS-CoV-2 virus infection, starting in Wuhan, China, and spreading throughout the world thereafter [1China’s first confirmed Covid-19 case traced back to November 17, in South China Morning Post, 13 marzo 2020 https://www.scmp.com/news/china/society/article/3074991/coronavirus-chinas-first-confirmed-covid-19-case-traced-back.Google Scholar, 2Coronavirus, il primo caso il 17 novembre: la ricostruzione che mette in difficoltà le autorità cinesi, Il Corriere della Sera, 14 marzo 2020.Google Scholar]. Event sequence The first COVID-19 infection case, referring to a 55-year-old man in Hubei province, was recorded on November 17, 2019 [1China’s first confirmed Covid-19 case traced back to November 17, in South China Morning Post, 13 marzo 2020 https://www.scmp.com/news/china/society/article/3074991/coronavirus-chinas-first-confirmed-covid-19-case-traced-back.Google Scholar, 2Coronavirus, il primo caso il 17 novembre: la ricostruzione che mette in difficoltà le autorità cinesi, Il Corriere della Sera, 14 marzo 2020.Google Scholar]. In the very beginning the agent was not identified as a new type of coronavirus, so that the news was reported by the Chinese government only on January 13, 2020 [[3]https://www.corriere.it/salute/20_marzo_14/coronavirus-primo-caso-17-novembre-ricostruzione-che-mette-difficolta-autorita-cinesi-87e75646-65e3-11ea-a287-bbde7409af03.shtmlGoogle Scholar]. Immediately after the epidemics became apparent so that Hubei province and the town of Wuhan were isolated and some 60 million people underwent a strict, army-secured quarantine which guaranteed the outbreak switch-off in about two months. Italy recorded its first COVID-19 pandemic event on January 31, 2020, when two tourists coming from China were found to be virus-positive in Rome [[4]WHO DECLARES 2019-NCOV ARD ‘PUBLIC HEALTH EMERGENCY OF INTERNATIONAL CONCERN’; PHIL GOV’T ISSUES TRAVEL BAN. Press Release 31 January, 2020. https://www.doh.gov.ph/doh-press-release/who-declares-2019-nCoV-ARD-public-health-emergency-of-international-concernGoogle Scholar]. On February 20, new outbreaks were detected in Codogno, Lodi province, Lombardy region, in terms of 16 infected people, summing up to 60 on the following day and causing the first deaths soon after [5Conte G. I primi due casi di coronavirus confermati in Italia. Il 2 febbraio l'evacuazione degli italiani da Wuhan, su ANSA, 31 gennaio 2020. https://www.ansa.it/canale_saluteebenessere/notizie/sanita/2020/01/30/conte-primi-due-casi-di-coronavirus-confermati-in-italia.-il-2-febbraio-levacuazione-degli-italiani-da-wuhan-_3698a086-c24e-470e-bba0-ef010daf4705.htmlGoogle Scholar, 6Coronavirus: 14 casi in Lombardia, due positivi ai primi test in Veneto, in la Repubblica, 21 febbraio 2020. https://www.repubblica.it/cronaca/2020/02/21/news/coronavirus_casi_veneto-249192220/Google Scholar, 7Due casi di coronavirus confermati dai primi due test a Padova, in Il Mattino (Padova), 21 febbraio 2020. https://www.ilmattino.it/primopiano/cronaca/coronavirus_padova_contagiati_veneto_ultime_notizie-5066356.htmlGoogle Scholar, 8Coronavirus, in isolamento Castiglione d’Adda, Codogno, Casalpusterlengo e altri 7 comuni, in Corriere della Sera (Milano), https://milano.corriere.it/notizie/cronaca/20_febbraio_21/coronavirus-castiglione-d-adda-codogno-isolamento-non-uscite-casa-non-andate-pronto-soccorso-4b0597ee-548e-11ea-9196-da7d305401b7.shtmlGoogle Scholar]. The patient identified as Case 1 was a 38-year old man from Codogno having respiratory tract infection signs. His wife and a close friend were also found COVID-19-positive [[5]Conte G. I primi due casi di coronavirus confermati in Italia. Il 2 febbraio l'evacuazione degli italiani da Wuhan, su ANSA, 31 gennaio 2020. https://www.ansa.it/canale_saluteebenessere/notizie/sanita/2020/01/30/conte-primi-due-casi-di-coronavirus-confermati-in-italia.-il-2-febbraio-levacuazione-degli-italiani-da-wuhan-_3698a086-c24e-470e-bba0-ef010daf4705.htmlGoogle Scholar] so that 13 municipalities in Lombardy and one in Veneto were immediately isolated to fulfil contagion containment procedures [[9]Matarese L. Coronavirus, obiettivo isolare il focolaio, in L'Huffington Post, 21 febbraio 2020. https://www.huffingtonpost.it/entry/coronavirus-obiettivo-isolare-il-focolaio_it_5e5036cbc5b629695f5a77f8Google Scholar]. Fig. 1, Fig. 2, Fig. 3 depict the evolution pattern of the epidemic in Italy throughout April 18, 2020 showing some slight positive signals, despite an overall long-lasting trend.Fig. 2New day-to-day (in yellow) SARS-CoV-2 swab-positive patients (left panel), death cases (right panel) and moving average of healed individuals on a continuous 5-day basis (middle panel, in blue) as of April 18, 2020 (Source: Data from the Ministry of Health processed by the ISS, modified). [[10]Misure urgenti in materia di contenimento e gestione dell'emergenza epidemiologica da COVID-19. Regione Lombardia. (20A01273) (GU Serie Generale n.47 del 25-02-2020) https://www.gazzettaufficiale.it/eli/id/2020/02/25/20A01273/sgGoogle Scholar)View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig. 3Admission trends to ICUs (left panel; the arrow shows the peak level reached on April 3) and ordinary wards (right panel; the March 29 arrow shows the 29,010 individual peak level) (Source: Sky TG 24 on data from the Ministry of Health processed by the ISS, modified) [[11]Ministero della salute, Report 19 aprile 2020. https://www.iss.it/coronavirusGoogle Scholar].View Large Image Figure ViewerDownload Hi-res image Download (PPT) When referring to the initial cases recorded in Lazio and in Lombardy, the epidemic has consistently followed parallel trends in the North (quite turbulent) and in the Center-South of Italy (much slower) and now, when freezing the official picture derived from data of the Ministry of Health processed by the Istituto Superiore di Sanità (ISS) as of April 18, 2020 (Table 1), we detect a huge difference between the two regions. Demographic data is quite different and strongly in favor of Lombardy in terms of number of provinces, municipalities, inhabitants, geographical surface and population density (people/km2) [[12]Sky TG 24 https://tg24.sky.it/cronaca/approfondimenti/foto/numero-contagi-coronavirus-italia.html#4 su dati forniti dal Ministero della salute, elaborati dell’Istituto Superiore di Sanità, https://www.iss.it/coronavirusGoogle Scholar]. In greater detail, when looking at results from the two regional capitals, accounting per se for the highest population density and consequently most relevant contagion spread risk, a paradox becomes immediately apparent: despite having fewer inhabitants than Rome (1,352,000 versus 2,873,000), Milan has suffered from a five-fold infection rate so far (see Table 2).Table 1Absolute number of SARS-CoV-2 infected individuals as of April 18, 2020 in Lombardy compared to Lazio. (Source: Data from the Ministry of Health processed by the ISS, modified). [10]Misure urgenti in materia di contenimento e gestione dell'emergenza epidemiologica da COVID-19. Regione Lombardia. (20A01273) (GU Serie Generale n.47 del 25-02-2020) https://www.gazzettaufficiale.it/eli/id/2020/02/25/20A01273/sgGoogle ScholarLOMBARDYTOWNCASESBergamo10,629Brescia11,758Como2,439Cremona5,407Lecco2,03Lodi2,714Monza Brianza4,042Milan15,546Mantova2,863Pavia3,536Sondrio937Varese2,106other / to be verified1,374TOTAL65,381LAZIOTOWNCASESRome4,018Frosinone505Rieti280Viterbo349Latina436other / to be verified80TOTAL5,668 Open table in a new tab Table 2Demographics from Lombardy and Lazio. (Source: Statistics from ISTAT - Istituto Nazionale di Statistica). [13]Statistiche ISTAT (Istituto Nazionale di Statistica). http://dati.istat.it/Google Scholar.Regionpopulationsurfacedensitynumber ofnumber ofinhabitantskm2inhabitants/km2municipalitiesprovincesLombardy10,060.57423,863.654221,50612Lazio5,879.08217,232.293413785 Open table in a new tab Which reason might underly such a clear difference? Despite discrepancies in timing, modality and rule severity, China and Italy adopted similar containment procedures, yet the spread of contagion was much faster in Northern than in Southern Italy (almost invariably comparable to Lazio). It is quite evident from Wuhan experience that the stricter the isolation rules for assessed or potentially infected people, the easier it is to prevent SARS-CoV-2 spreading. This was the case in Rome where, immediately after being diagnosed, the two Chinese infected persons were admitted into the Spallanzani Hospital, a 40-year-renowned research and care center for infectious diseases and all their travel-mates and contacts were identified and isolated into the Cecchignola military citadel on the outskirts of Rome. All over Lombardy, instead, due to the lack of symptoms of infected people for several days or even weeks, virus spread was much wider, thus reaching out to Veneto and Emilia-Romagna regions, and presumably required longer to develop earlier symptoms after being infected. This might be explained by the fact that the two Chinese cases in Rome were older than Case 1 in Codogno (i.e. 68 vs 38 years of age). The former followed an easily traceable tourist itinerary while the latter moved around quite easily and extensively among regions making it impossible to track down all contacts. Moreover, the evidence so far seems to indicate that, besides being burdened by higher mortality due to the frequent coexistence of other diseases, older subjects are more easily infected and severely ill and this might have caused weakness symptoms quite soon preventing the Chinese patients in Rome from moving around [13Statistiche ISTAT (Istituto Nazionale di Statistica). http://dati.istat.it/Google Scholar, 14La Repubblica, 4 aprile 2020. Troppa gente in giro a Milano. https://milano.repubblica.it/cronaca/2020/04/04/news/coronavirus_milano_sala_troppa_gente_in_giro_controlli-253101858/Google Scholar]. There are also anecdotical reports concerning a shorter incubation period in the elderly which might add to the above, yet further studies are still needed to validate such hypothesis. Are there any other possible explanations for accelerated coronavirus spread in Lombardy? Indeed, the most affected area in the region, including Milan and its hinterland, is quite rich in farms and industries asking for intensive daily commuting and in the early phases of the epidemic most activities were still in place and partially stopped only about two weeks later. In fact, beginning of March, after the outbreak had already shown its threatening potential, only “crucial” activities were allowed to go on including food and drug chains, logistic support providers, general practitioner (GP) offices, which anyway involved some 40% of the working population [[14]La Repubblica, 4 aprile 2020. Troppa gente in giro a Milano. https://milano.repubblica.it/cronaca/2020/04/04/news/coronavirus_milano_sala_troppa_gente_in_giro_controlli-253101858/Google Scholar]. So considerable train, metro and bus commuting, relatively late recognition and multiple outbreak sites might have favored such a large infection spreading pattern in Northern Italy. Two more observations might also be taken into account, albeit requiring further validation by controlled studies: (i) a large number of treatment-resistant pneumonia events occurring already in January were reported by GPs a posteriori, i.e. after SARS-CoV-2 outbreak, and might reflect the presence in the area of potentially unrecognized carriers responsible for the exponential spreading of coronavirus infection [[15]Gentile Sandro Strollo Felice Ceriello Antonio COVID-19 infection in Italian people with diabetes: Lessons learned for our future (an experience to be used).Diabetes Res Clin Pract. 2020; 162: 108137https://doi.org/10.1016/j.diabres.2020.108137Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar] and (ii) more severe fine dust pollution and less favorable hygrometric and barometric environmental conditions characterize the whole Po Valley as compared to the rest of Italy, as also apparent from European Space Agency reports [17ESA. Coronavirus: nitrogen dioxide emissions fall in Italy http://www.esa.int/Space_in_Member_States/Italy/Coronavirus_calano_in_Italia_le_emissioni_di_diossido_di_azotoGoogle Scholar, 18Position paper. Relazione circa l’effetto dell’inquinamento da particolato atmosferico e la diffusione di virus nella popolazione. https://www.actu- environnement.com/media/pdf/news-35178-covid-19.pdfGoogle Scholar]. Finally, as far as type 2 diabetes mellitus (T2DM) is concerned, we now have to underline that, as recently pointed out by two Italian groups [15Gentile Sandro Strollo Felice Ceriello Antonio COVID-19 infection in Italian people with diabetes: Lessons learned for our future (an experience to be used).Diabetes Res Clin Pract. 2020; 162: 108137https://doi.org/10.1016/j.diabres.2020.108137Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 19Onder G. Rezza G. Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy.JAMA. 2020; (Epub 2020/03/24 PubMed PMID: 32203977)Crossref PubMed Scopus (2607) Google Scholar] and reported by Chinese scientists directly involved in the management of COVID-19 infection [20Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020:1–13. Epub 2020/02/29. PubMed PMID: 32109013.Google Scholar, 21Shi H. Han X. Jiang N. Cao Y. Alwalid O. Gu J Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study.Lancet Infect Dis. 2020; 20 (Epub 2020/02/28 PubMed PMID: 32105637): 425-434Abstract Full Text Full Text PDF PubMed Scopus (2239) Google Scholar], the disease is extremely frequent and associates with a higher mortality rate in hospitalized patients (Table 3) [[22]Istituto Superiore di Sanità. Characteristics of SARS-CoV-2 patients dying in Italy Report based on available data on April 20th, 2020. https://www.epicentro.iss.it/en/coronavirus/bollettino/Report-COVID-2019_20_april_2020.pdfGoogle Scholar]. Such phenomenon, which was further confirmed in Italian patients by the most recent bulletin from the ISS, had become apparent, despite different prevalence estimates, since the very beginning of the epidemic in China [[15]Gentile Sandro Strollo Felice Ceriello Antonio COVID-19 infection in Italian people with diabetes: Lessons learned for our future (an experience to be used).Diabetes Res Clin Pract. 2020; 162: 108137https://doi.org/10.1016/j.diabres.2020.108137Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar].Table 3Absolute and relative prevalence of most common pre-existing cardiovascular and metabolic comorbidities as retrieved from available charts concerning 1,890 COVID-19-positive people dying in Italian hospitals. [21]Shi H. Han X. Jiang N. Cao Y. Alwalid O. Gu J Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study.Lancet Infect Dis. 2020; 20 (Epub 2020/02/28 PubMed PMID: 32105637): 425-434Abstract Full Text Full Text PDF PubMed Scopus (2239) Google Scholar.DiseaseN%Ischemic heart disease51827.4Atrial Fibrillation41121.7Heart failure29815.8Stroke20610.9Hypertension1,31769.7Type 2-Diabetes60331.9Obesity23012.2 Open table in a new tab Diabetes and uncontrolled glycaemia had already been reported as significant predictors of severity and deaths in patients infected with different viruses as well, including the 2009 pandemic influenza A (H1N1) [[23]Schoen Karla, Horvat Natally, Guerreiro Nicolau F.C., de Castro Isac, de Giassi Karina S. Spectrum of clinical and radiographic findings in patients with diagnosis of H1N1 and correlation with clinical severity. BMC Infect Dis. 2019;19(1).Google Scholar], SARS-CoV [[24]Yang J.K. Feng Y. Yuan M.Y. Yuan S.Y. Fu H.J. Wu B.Y. Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS.Diabet Med. 2006; 23 (Epub 2006/06/09 PubMed PMID: 16759303): 623-628Crossref PubMed Scopus (444) Google Scholar] and MERS-CoV [[25]Banik Gouri Rani Alqahtani Amani Salem Booy Robert Rashid Harunor Risk factors for severity and mortality in patients with MERS-CoV: Analysis of publicly available data from Saudi Arabia.Virol. Sin. 2016; 31: 81-84https://doi.org/10.1007/s12250-015-3679-zCrossref PubMed Scopus (79) Google Scholar]. SARS-CoV-2 Infection in individuals with DM is expected to trigger higher stress conditions, with greater release of hyperglycemic hormones, e.g., glucocorticoids and catecholamines, leading to increased blood glucose levels and abnormal glucose variability [[26]Aihong Wang Zhao Weibo Xu. Jianwen Zhangrong, Gu Timely blood glucose management for the outbreak of 2019 novel coronavirus disease (COVID-19) is urgently needed.Diabetes Res Clin Pract. 2020; 162108118Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar]. On the other hand, according to a retrospective study from Wuhan some 10% COVID-19-positive patients with T2DM suffered at least one hypoglycemic event (<3.9 mmol/L) [[27]Zhou J. Tan J. Diabetes patients with COVID-19 need better care.Metabolism. 2020 Mar; 24154216https://doi.org/10.1016/j.metabol.2020.154216Abstract Full Text Full Text PDF Scopus (83) Google Scholar]. Notoriously, hypoglycemia mobilizes pro-inflammatory monocytes and increases platelet reactivity, thus contributing to a higher cardiovascular mortality in patients with DM [[28]Hussain A. Bhowmik B. do Vale Moreira N.C. COVID-19 and Diabetes: Knowledge in Progress.Diabetes Res Clin Pract. 2020; 162108142https://doi.org/10.1016/j.diabres.2020.108142Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar]. In addition, hyperglycemia and insulin resistance enhance the build-up of glycosylation end products (AGEs) and pro-inflammatory cytokines causing severe oxidative stress and increased inflammation-related adhesion molecule release [29Iqbal A, Prince LR, Novodvorsky P, Bernjak A, Thomas MR, Birch L, et al. Effect of Hypoglycemia on Inflammatory Responses and the Response to Low-Dose Endotoxemia in Humans. J Clin Endocrinol Metab. 2019;104(4):1187-99. Epub 2018/09/27. doi: 10.1210/jc.2018-01168. PubMed PMID: 30252067; PubMed Central PMCID: PMCPMC6391720.Google Scholar, 30Knapp Sylvia Diabetes and Infection: Is There a Link? - A Mini-Review.Gerontology. 2013; 59: 99-104https://doi.org/10.1159/000345107Crossref PubMed Scopus (199) Google Scholar, 31Petrie John R. Guzik Tomasz J. Touyz Rhian M. Diabetes, Hypertension, and Cardiovascular Disease: Clinical Insights and Vascular Mechanisms.Can J Cardiol. 2018; 34: 575-584https://doi.org/10.1016/j.cjca.2017.12.005Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar]. All this may in fact contribute to the mechanisms underlying the greater susceptibility to infections and the worse outcomes thereof observed in patients with DM [[30]Knapp Sylvia Diabetes and Infection: Is There a Link? - A Mini-Review.Gerontology. 2013; 59: 99-104https://doi.org/10.1159/000345107Crossref PubMed Scopus (199) Google Scholar]. Mostly based on in vitro studies, hyperglycemia associates with several immune system defects, including inhibited lymphocyte proliferative response to different kinds of stimuli [32Geerlings SE, Hoepelman AI. Immune dysfunction in patients with diabetes mellitus (DM). FEMS Immunol Med Microbiol. 1999;26(3-4):259-65. Epub 1999/11/27. doi: 10.1111/j.1574-695X.1999.tb01397.x. PubMed PMID: 10575137.)Google Scholar, 33Moutschen MP, Scheen AJ, Lefebvre PJ. Impaired immune responses in diabetes mellitus: analysis of the factors and mechanisms involved. Relevance to the increased susceptibility of diabetic patients to specific infections. Diabete Metab. 1992;18(3):187-201. Epub 1992/05/01. PubMed PMID: 1397473.Google Scholar], and impaired monocyte/macrophage and neutrophil functions [[30]Knapp Sylvia Diabetes and Infection: Is There a Link? - A Mini-Review.Gerontology. 2013; 59: 99-104https://doi.org/10.1159/000345107Crossref PubMed Scopus (199) Google Scholar]. In vitro studies have shown that pulmonary epithelial cells exposure to high glucose concentrations significantly increases influenza virus infection and replication, pointing to hyperglycemia-enhanced viral replication in vivo [[34]Kohio Hinissan P. Adamson Amy L. Glycolytic control of vacuolar-type ATPase activity: A mechanism to regulate influenza viral infection.Virology. 2013; 444: 301-309https://doi.org/10.1016/j.virol.2013.06.026Crossref PubMed Scopus (76) Google Scholar]. In animal models, structural lung changes have been related to diabetes, such as augmented vasculature permeability and collapsed alveolar epithelium [[35]Dunn E.J. Grant P.J. Type 2 diabetes: an atherothrombotic syndrome.Curr Mol Med. 2005; 5 (Epub 2005/05/17. 10.2174/1566524053766059 PubMed PMID: 15892651): 323-332Crossref PubMed Scopus (71) Google Scholar]. Finally, abnormal delayed-type hypersensitivity reaction and complement activation dysfunction [[36]Lange P. Groth S. Kastrup J. Mortensen J. Appleyard M. Nyboe J. et al.Diabetes mellitus, plasma glucose and lung function in a cross-sectional population study.Eur Respir J. 1989; 2 (Epub 1989/01/01 PubMed PMID: 2651148): 14-19Crossref PubMed Google Scholar] have been reported in patients with DM. All of the above suggests that the greatest possible attention should be paid to the high risk for more severe lung involvement pending on people with DM during COVID-19 infection, due to a significantly lower forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) in the presence of raised glucose levels [[37]Song Z., Xu Y., Bao L., Zhang L., Yu P., Qu Y. From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses. 2019 Jan 14;11(1). pii: E59. doi: 10.3390/v11010059.Google Scholar]. So which pathogenetic elements underly higher susceptibility to COVID-19 disease and mortality rate in people with DM? The virus itself and its toxins precipitate a cytokine thunderstorm exacerbating hypercoagulation in patients with DM [20Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020:1–13. Epub 2020/02/29. PubMed PMID: 32109013.Google Scholar, 34Kohio Hinissan P. Adamson Amy L. Glycolytic control of vacuolar-type ATPase activity: A mechanism to regulate influenza viral infection.Virology. 2013; 444: 301-309https://doi.org/10.1016/j.virol.2013.06.026Crossref PubMed Scopus (76) Google Scholar] who, by definition, face a clear-cut prothrombotic state [[35]Dunn E.J. Grant P.J. Type 2 diabetes: an atherothrombotic syndrome.Curr Mol Med. 2005; 5 (Epub 2005/05/17. 10.2174/1566524053766059 PubMed PMID: 15892651): 323-332Crossref PubMed Scopus (71) Google Scholar], further aggravated by chronic low-grade inflammation causing atherosclerosis-related endothelial dysfunction and insulin-resistance associated arterial hypertension [[36]Lange P. Groth S. Kastrup J. Mortensen J. Appleyard M. Nyboe J. et al.Diabetes mellitus, plasma glucose and lung function in a cross-sectional population study.Eur Respir J. 1989; 2 (Epub 1989/01/01 PubMed PMID: 2651148): 14-19Crossref PubMed Google Scholar]. All above-mentioned phenomena are known to become more and more severe as age increases and this is in line with the observation that octogenarian individuals are mostly affected by SARS-CoV-2 disease [[19]Onder G. Rezza G. Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy.JAMA. 2020; (Epub 2020/03/24 PubMed PMID: 32203977)Crossref PubMed Scopus (2607) Google Scholar]. With respect to that, an issue deserving special attention is the quite similar SASR-CoV-2 infection rate in people without or with DM [[25]Banik Gouri Rani Alqahtani Amani Salem Booy Robert Rashid Harunor Risk factors for severity and mortality in patients with MERS-CoV: Analysis of publicly available data from Saudi Arabia.Virol. Sin. 2016; 31: 81-84https://doi.org/10.1007/s12250-015-3679-zCrossref PubMed Scopus (79) Google Scholar] in front of a much greater severity of the disease as reported by the Italian ISS in the latter. At this point we also feel like underlining that some hypoglycemic treatment strategies might turn out to be protective. Dipeptidyl-dipeptidase-4 (DPP-4) was shown, in fact, to be the primary receptor of MERS-CoV [[37]Song Z., Xu Y., Bao L., Zhang L., Yu P., Qu Y. From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses. 2019 Jan 14;11(1). pii: E59. doi: 10.3390/v11010059.Google Scholar]: the possibility that DPP-4 also acts as a receptor for SARS-CoV-2 warrants investigation and, should this be the case, in agreement with the hypothesis put forward by Iacobellis [[38]Iacobellis G. COVID-19 and diabetes: Can DPP-4 inhibition play a role ?.Diabetes Res Clin Pract. 2020; 26108125https://doi.org/10.1016/j.diabres.2020.108125Abstract Full Text Full Text PDF Scopus (211) Google Scholar], DPP-4 inhibitors, well-renowned treatment tools in T2DM, should be explored for their anti-viral potential in the human [[15]Gentile Sandro Strollo Felice Ceriello Antonio COVID-19 infection in Italian people with diabetes: Lessons learned for our future (an experience to be used).Diabetes Res Clin Pract. 2020; 162: 108137https://doi.org/10.1016/j.diabres.2020.108137Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar]. Opposite to that, it has been recently hypothesized that Sodium-Glucose-Transporter-2 inhibitors (SGLT-2i), Glucagon-Like-Peptide-1 Receptor Agonists (GLP-1RAs), Pioglitazone and even Insulin might induce an over-expression of the ACE2 receptor which was also found to bind to coronaviruses in the alveoli [[39]Pal R. Bhadada S.K. Should anti-diabetic medications be reconsidered amid COVID-19 pandemic?.Diabetes Res Clin Pract. 2020; 163108146https://doi.org/10.1016/j.diabres.2020.108146Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar], and therefore increase the risk for a more severe expression of SARS-CoV-2 infection in people with diabetes [[40]Ceriello A. Stoian A.P. Rizzo M. COVID-19 and diabetes management: what should be considered?.Diabetes Res Clin Pract. 2020; 163108151https://doi.org/10.1016/j.diabres.2020.108151Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar]. Corticosteroid utilization also requires special attention with respect to COVID-19 disease severity in people with DM [[41]World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. Interim guidance, 13 March 2020 Geneva2020 [28/03/2020]. Available from: https://www.thelancet.com/action/showPdf?pii=S0140- 6736%2820%2930317-2.Google Scholar]. Acute lung damage and acute respiratory distress syndrome (ARDS) are partly due to the host immune response and corticosteroids were broadly used in SARS-CoV and MERS-CoV infections [42Russell C.D. Millar J.E. Baillie J.K. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.Lancet. 2020; 395 (Epub 2020/02/12. 10.1016/S0140-6736(20)30317-2 PubMed PMID: 32043983): 473-475Abstract Full Text Full Text PDF PubMed Scopus (1382) Google Scholar, 43Arabi Yaseen M. Balkhy Hanan H. Hayden Frederick G. Bouchama Abderrezak Luke Thomas Baillie J. Kenneth Al-Omari Awad Hajeer Ali H. Senga Mikiko Denison Mark R. Nguyen-Van-Tam Jonathan S. Shindo Nahoko Bermingham Alison Chappell James D. Van Kerkhove Maria D. Fowler Robert A. Middle East Respiratory Syndrome.N Engl J Med. 2017; 376: 584-594https://doi.org/10.1056/NEJMsr1408795Crossref PubMed Scopus (277) Google Scholar] due to their ability to suppress histologically proven virus-dependent lung inflammation with diffuse alveolar damage [[44]Jaber Emami Pasutto Franco M. Mercer John R. Jamali Fakhreddin. Inhibition of insulin metabolism by hydroxychloroquine and its enantiomers in cytosolic fraction of liver homogenates from healthy and diabetic rats.Life Sci. 1998; 64: 325-335Crossref Scopus (39) Google Scholar]. However, they also inhibit immunity and pathogen clearance and, in the face of very little benefit if so ever, have been associated with delayed viral RNA clearance or increased mortality and rate of complications, including diabetes, psychosis, and avascular necrosis [[42]Russell C.D. Millar J.E. Baillie J.K. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.Lancet. 2020; 395 (Epub 2020/02/12. 10.1016/S0140-6736(20)30317-2 PubMed PMID: 32043983): 473-475Abstract Full Text Full Text PDF PubMed Scopus (1382) Google Scholar]. Due to all the above, the interim guidance from the WHO on clinical management of severe acute respiratory infection advises against the use of corticosteroids upon suspicion of SARS-CoV-2 infection outside clinical trials [[45]Arabi YM, Mandourah Y, Al-Hameed F, Sindi AA, Almekhlafi GA, Hussein MA, et al. Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med. 2018;197(6):757-67. Epub 2017/11/22. doi: 10.1164/rccm.201706- 1172OC. PubMed PMID: 29161116.Google Scholar], yet corticosteroids were extensively utilized before that in at least 34% of the large number of Northern Italian hospitalized patients [[46]Gentile S, Strollo F, Ceriello A. The need for diabetes care customization in the ICU at the time of SARS-CoV-2 outbreak. Diab Therapy 2020, in pressGoogle Scholar]. At analysing the growth curve of coronavirus infection in Italy, the massive referral to the hospitals of so many people within a very a short period strikes the eye when compared to the small number of hospitalized patients in the South (Figura 4). In the stormy and overcrowded emergency conditions faced by health professionals at the start of the epidemic in the absence of any experience with treating COVID-19 disease, a broader recourse to high doses of corticosteroids most likely occurred than later on, when in fact better treatment strategies were identified and emergency departments were less congested. It can be assumed that the above mentioned logistic and environmental factors strongly affected clinical course and mortality rates of COVID-19-infected people and even more in those with DM. Indeed, Fig. 4 clearly shows that death rate was significantly higher in infected Northern Italy inhabitants than in their Southern counterpart (i.e. 17.2% vs 5.5%, respectively). According to current protocols, subject to the exceptions needed for treatment personalization, the use of corticosteroids is extremely limited if so ever. This might also help healthcare teams adopt an intensive, fully integrated therapeutic approach for their patients with DM, especially those in the ICUs, involving drugs expected to prevent at their best both hypoglycemic events and dramatic hyperglycemic spikes contributing to marked glycemic variability, i.e. a severe mortality risk driver [[47]Ceriello A. Monnier L. Owens D. Glycemic variability in diabetes: clinical and therapeutic implications.Lancet Diab Endocrinol. 2019; 7: 221-230Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar] (see Fig. 5).Fig. 5Territorial differences in SARS-CoV-2 infection within Italy as of April 16, 2020 (Source: Data from the Ministry of Health processed by the ISS, modified) [[16]ISS, Characteristics of SARS-CoV-2 patients dying in Italy Report based on available data on April 16, 2020, https://www.epicentro.iss.it/en/coronavirus/bollettino/Report-COVID-2019_16_april_2020.pdfGoogle Scholar].View Large Image Figure ViewerDownload Hi-res image Download (PPT) A final report coming from TOSCA, a recent nationwide study on people with T2DM, known to affect mostly older patients who, in turn, are at higher risk for severe COVID-19 disease, shows that a high adherence to the Mediterranean diet is significantly more frequent among people living in the southern regions of Italy [[48]Vitale M, Masulli M, Calabrese I, Rivellese AA, Bonora E, Signorini S, et al.; TOSCA.IT Study Group. Impact of a Mediterranean Dietary Pattern and Its Components on Cardiovascular Risk Factors, Glucose Control, and Body Weight in People with Type 2 Diabetes: A Real-Life Study. Nutrients. 2018 Aug 10;10(8). pii: E1067. doi: 10.3390/nu10081067Google Scholar]. The latter, however, display a slightly higher phenolic acid and lignan intake due to a higher consumption of cereals and legumes and a slightly lower total polyphenol intake as flavonoids and stilbenes due to lower wine consumption [[49]Vitale M, Masulli M, Rivellese AA, Bonora E, Cappellini F, Nicolucci A, et al.; TOSCA.IT Study Group. Dietary intake and major food sources of polyphenols in people with type 2 diabetes: The TOSCA.IT Study. Eur J Nutr. 2018 Mar;57(2):679-688. doi: 10.1007/s00394-016-1355-1. Epub 2016 Dec 21.Google Scholar]. This takes on a particular significance when comparing the absolute and relative death rate of subjects with T2DM in Lombardy (11,384 deaths; 56.9% of infected individuals) to that observed in Lazio (259 deaths; 1.3% of infected individuals). Might this add to the picture? At the moment, ours can only be taken as speculation but we strongly believe that also lifestyle components deserve further investigation with respect to COVID-19 disease. In conclusion, based on official Ministry of Health and ISS statements we are fully aware that:•a strikingly different trend was observed for SARS-CoV-2 infection between Northern and Southern Italy;•strict containment rules are the best way to prevent SARS-CoV-2 epidemics from spreading;•territory-oriented medicine might play an effective guardian role and should therefore be listened to and strengthened;•people with T2DM are more susceptible to SARS-CoV-2 infection, with twice as high mortality risk as metabolically healthy people;•high amounts of polyphenol-derived antioxidants from cereals and legumes typical of the Mediterranean diet might help to stop SARS-CoV-2 infection from spreading. To borrow from Plutarch, the conditions described above are asymmetrically parallel. So, asymmetry proved to be detrimental to Italy, and especially its Northern part and to somewhat spare the Central and Southern areas so far, whose ancient Greek culture-derived lifestyle might have positively, albeit almost unexplainedly and inadvertently, influenced the susceptibility to coronavirus infection.

Diabetes Research and Clinical Practice

May 12, 2020
Felice Strollo + 2

(1) Background: Diagnostic testing for cystic fibrosis (CF) is based on a sweat chloride test (SCT) considering the appropriate signs and symptoms of the disease and results of a gene mutation analysis. In 2014, the Istituto Superiore di Sanità (ISS) established a pilot Italian external quality assessment program for CF SCT (Italian EQA-SCT), which is now a third party service carried out by the ISS. (2) Methods: The ongoing scheme is prospective, enrollment is voluntary, and the payment of a fee is required. Results are shared through a dedicated web-facility. Assessment covers the analysis, interpretation, and reporting of results. (3) Results: Thirteen, fifteen, sixteen, and fifteen different laboratories, respectively, participated from 2015 to 2016 and from 2018 to 2019 in the Italian EQA-SCT scheme. Eleven different laboratories participated each year in all four rounds of the Italian EQA-SCT. (4) Conclusions: The overall results obtained from the laboratories participating constantly clearly show that their qualitative and quantitative performance improved significantly. This is due to the opportunity—after receiving the EQA results—to constantly review their performance and address any inconsistencies. We firmly believe that participation in the EQA program will improve the quality of participating laboratories and that EQA participation should become mandatory as a fundamental requirement for laboratory accreditation.

Coronavirus disease-2019 (COVID-19) is the infectious disease caused by the recently discovered coronavirus SARS-CoV-2. The first case of COVID-19 was reported to the World Health Organization (WHO) by Chinese authorities on December 31st 2019 as a result of a patient suffering pneumonia in Wuhan City, Hubei Province, China. Following a rapid spread in China, new outbreaks occurred in northern Italy and in several European countries. On March 12th 2020 WHO announced COVID-19 outbreak a pandemic. COVID-19 results in a respiratory infection characterized by mild to severe symptoms such as dry cough, fever and difficulty breathing which can appear up to about 14 days after exposure to the virus. According to National Center for Immunization and Respiratory Diseases (NCIRD) high-risk categories for severe illness from COVID-19 are people aged 65 years and older, who live in a nursing home or long-term care facility, immunocompromised, or people with underlying medical conditions, particularly if not well controlled, including chronic lung diseases, serious heart conditions, type 1 or type 2 diabetes, liver diseases, chronic kidney disease undergoing dialysis and severe obesity (body mass index [BMI] of 40 or higher). Until now, there are no data in the literature reporting that subjects with obesity have a higher risk of getting COVID-19; however, since obesity is known to increase the risk of developing severe forms of respiratory failure, it could be hypothesized that subjects with obesity could be at risk of serious illness if infected. In particular, according to the Intensive Care National Audit & Research Centre (ICNARC) report on COVID-19 in critical care of United Kingdom (March 27th 2020), it was observed that 72.1% of 775 patients with confirmed COVID-19 were overweight or obese and that among patients with BMI > 30 who had undergone intensive care, 60.9% of them died [[1]www.icnarc.orgDate accessed: April 3, 2020Google Scholar]. In addition, according to Italian data published on April 6th 2020 by the Istituto Superiore di Sanità (ISS), an overall prevalence of obesity of 10.0% was found among 1290 patients died for whom there was the availability of medical records [[2]www.epicentro.iss.it/coronavirus/sars-cov-2-decessi-italiaDate accessed: April 7, 2020Google Scholar]. In this retrospective cohort study in a single French center evaluating 124 consecutive patients admitted in intensive care for SARS-CoV-2, it has been observed that obesity (BMI >30 kg/m2) and severe obesity (BMI >35 kg/m2) were present in 47.6% and 28.2% of cases, respectively, that patients who required invasive mechanical ventilation (IMV) increased with BMI categories (p < 0.01) and it was greatest in patients with BMI >35 kg/m (85.7%) [[3]Simonnet A. Chetboun M. Poissy J. Raverdy V. Noulette J. Duhamel A. et al.High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation.Obesity (Silver Spring). 2020 Apr 9; https://doi.org/10.1002/oby.22831Crossref PubMed Scopus (1168) Google Scholar]. As well known, obesity represents a state of low grade chronic inflammation that can contribute to the onset of metabolic diseases (dyslipidemia, insulin resistance and type 2 diabetes mellitus [T2DM]) and can modify innate and adaptive immune responses, making the immune system more vulnerable to infections and less responsive to vaccinations, antivirals and antimicrobial drugs [[4]Dhurandhar N.V. Bailey D. Thomas D. Interaction of obesity and infections.Obes Rev. 2015; 16: 1017-1029https://doi.org/10.1111/obr.12320Crossref PubMed Scopus (93) Google Scholar]. Recent findings have highlighted the substantial impact that obesity have on immunity and pathogen defense, including the disruption of lymphoid tissue integrity; alterations in leukocyte development, phenotypes and activity; and the coordination of innate and adaptive immune responses. In particular, obesity has been shown to impair memory CD8+ T cell responses to influenza virus infection, resulting in increased mortality, viral titers in lung, and worsened lung pathology. These adverse effects were associated with an obesity-induced failure to maintain influenza-specific CD8+ memory T cells, which are essential in ensuring vaccine efficacy [[5]Karlsson E.A. Sheridan P.A. Beck M.A. Diet-induced obesity in mice reduces the maintenance of influenza-specific CD8+ memory T cells.J Nutr. 2010; 140: 1691-1697https://doi.org/10.3945/jn.110.123653Crossref PubMed Scopus (91) Google Scholar]. Low-grade inflammation is determined by a condition of adipocyte hypoxia and dysfunction, that results in an exuberant secretion of pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin (IL) 1β and IL-6 and the recruitment of immune cells macrophage, T-cell and B-cell, creating an auto-regenerating inflammation loop [[6]Vieira Potter V.J. Inflammation and macrophage modulation in adipose tissues.Cell Microbiol. 2014; 16: 1484-1492https://doi.org/10.1111/cmi.12336Crossref PubMed Scopus (114) Google Scholar]. Indeed increased circulating levels of pro-inflammatory cytokines, such as TNF-α, IL-6, or C-reactive protein, have been reported in overweight and obese adults [[7]Park H.S. Park J.Y. Yu R. Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6.Diabetes Res Clin Pract. 2005; 69: 29-35https://doi.org/10.1016/j.diabres.2004.11.007Abstract Full Text Full Text PDF PubMed Scopus (628) Google Scholar]. Having so far limited scientific evidence regarding the pathophysiological mechanisms linking obesity and COVID-19, some interesting information can be extrapolated from studies conducted on subjects with H1N1 infection: it has been shown that subjects with obesity compared with normal-weight individuals evince in H1N1 infection more intense IL-8 release, which is a chemokine of innate immunity involved in chemotaxis, being a major chemokine for neutrophil activation and migration into tissue, a mechanism involved in response to infection [[8]Hagau N. Slavcovici A. Gonganau D.N. Oltean S. Dirzu D.S. Brezoszki E.S. et al.Clinical aspects and cytokine response in severe H1N1 influenza A virus infection.Crit Care. 2010; 14: R203https://doi.org/10.1186/cc9324Crossref PubMed Google Scholar]. In parallel, one of the most important mechanisms underlying the severity of lung disease in COVID-19 is represented by the “cytokine storm” which can lead to acute respiratory distress syndrome or even multiple organ failure. It represents a phenomenon of immune hyper activation very similar to Cytokine-release syndrome (CRS) typically described in the setting of T cell-engaging immunotherapy and characterized by increased levels of IL-6, interferon (IFN) γ and other cytokines, causing consequences and symptoms related to immune activation, ranging from general malaise, myalgia and fever to severe organ toxicity, respiratory failure and death [[9]Chen C. Zhang X.R. Ju Z.Y. He W.F. Advances in the research of cytokine storm mechanism induced by Corona virus disease 2019 and the corresponding immunotherapies.Zhonghua Shao Shang Za Zhi. 2020; 36E005https://doi.org/10.3760/cma.j.cn501120-20200224-00088Crossref PubMed Google Scholar]. In support of the importance of counteracting the inflammatory response to avoid the progression of COVID-19, the use of tocilizumab in subjects with severe respiratory impairment is being tested with encouraging results. Tocilizumab is a recombinant humanized monoclonal antibody, which binds the human IL-6 receptor, inhibiting its signal transduction, currently used for rheumatoid arthritis, but its efficacy has also been demonstrated against other forms of lung immune-related pneumopathy [[10]Stroud C.R. Hegde A. Cherry C. Naqash A.R. Sharma N. Addepalli S. et al.Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade.J Oncol Pharm Pract. 2019; 25: 551-557https://doi.org/10.1177/1078155217745144Crossref PubMed Scopus (160) Google Scholar]. Whereas, considering that subjects with obesity have a proinflammatory milieu, it is expected that COVID-19 could further exacerbate inflammation exposing them to higher levels of circulating inflammatory molecules compared to lean human subjects. This could explain the increased risk of severe complications of COVID-19 for subjects with obesity. Obesity-related comorbidities could also represent an additional risk factor for complications of COVID-19 in obesity. In fact T2DM, hypertension and cardiovascular diseases were frequently detected in subjects died from COVID-19 in Italy, suggesting that they could increase the risk of mortality for COVID-19. Regarding T2DM, four risk factors for diabetic patients with COVID-19, compared to COVID patients without diabetes were proposed, which can increase the risk of poor outcomes: susceptibility to hyperglycemia from corticosteroid therapy, inadequate glycemic control, lack of contact with healthcare professionals and inappropriate discontinuation of an angiotensin receptor blocker (ARB) or an angiotensin converting enzyme (ACE) inhibitor, which individually or synergistically could justify the worst prognosis in the patients with T2DM and COVID-19 [[11]Klonoff D.C. Umpierrez G.E. COVID-19 in patients with diabetes: risk factors that increase morbidity.Metabolism. 2020 Apr; 7: 154224https://doi.org/10.1016/j.metabol.2020.154224Abstract Full Text Full Text PDF Scopus (56) Google Scholar]. In fact, it has also been questioned that ACE inhibitors or ARBs, usually used as treatment for hypertension, could increase the risk of SARS-CoV-2 infection and COVID-19 severity, since they increase the expression of ACE 2 whose receptor is used by the virus SARS-CoV-2 to enter into the host cell [[12]Fang L. Karakiulakis G. Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?.Lancet Respir Med. 2020; 8e21https://doi.org/10.1016/S2213-2600(20)30116-8Abstract Full Text Full Text PDF PubMed Scopus (1827) Google Scholar]. However, currently there are no sufficient data to support this hypothesis and therefore The American Heart Association (AHA), the Heart Failure Society of America (HFSA), and the American College of Cardiology (ACC) released a statement recommending continuation of these drugs for patients already receiving them for heart failure, hypertension, or ischemic heart disease. In addition, subjects with obesity often suffer from chronic obstructive bronchopathy, asthma, hypoventilation syndrome, obstructive sleep apnea and other mechanical anomalies due to excess of thoracic and abdominal fat mass that could be a “breeding ground” for respiratory complications [[13]Rabec C. de Lucas Ramos P. Veale D. Respiratory complications of obesity.Arch Bronconeumol. 2011; 47: 252-261https://doi.org/10.1016/S1579-2129(11)70061-1Crossref PubMed Scopus (0) Google Scholar]. Another clinical condition frequently encountered in subjects with obesity is metabolic associated fatty liver disease (MAFLD) defined by the evidence of hepatic steatosis, in addition to one of the following three criteria: overweight/obesity, presence of T2DM or evidence of metabolic dysregulation [[14]Eslam M. Newsome P.N. Anstee Q.M. Targher G. Gomez M.R. Zelber-Sagi S. et al.A new definition for metabolic associated fatty liver disease: an international expert consensus statement.J Hepatol. 2020 Apr 8; (pii: S0168-8278(20)30201-4)https://doi.org/10.1016/j.jhep.2020.03.039Abstract Full Text Full Text PDF PubMed Scopus (1206) Google Scholar]. In MAFLD patients, especially those with obesity, IL-6 levels independently predicted increasing liver inflammation, which might play an additive/synergistic role in promoting greater severity of COVID-19 [[15]Van der Poorten D. Milner K.L. Hui J. Hodge A. Trenell M.I. Kench J.G. et al.Visceral fat: a key mediator of steatohepatitis in metabolic liver disease.Hepatology. 2008; 48: 449-457https://doi.org/10.1002/hep.22350Crossref PubMed Scopus (438) Google Scholar]. In this regard, in a study conducted in three Chinese hospitals, 66 patients with MAFLD evaluated by computed tomography and laboratory-confirmed COVID-19 were analyzed [ [16]Zheng K.I. Gao F. Wang X.B. Sun Q.F. Pan K.H. Wang T.Y. Ma H.L. Liu W.Y. George J. Zheng M.H. Obesity as a risk factor for greater severity of COVID-19 in patients with metabolic associated fatty liver disease.Metabolism. 2020 Apr 19; ([Epub ahead of print] PubMed PMID: 32320741; PubMed Central PMCID: PMC7166301): 154244https://doi.org/10.1016/j.metabol.2020.154244Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar].It has been observed that: MALFD patients with obesity had more severe COVID-19 disease than non-obese ones (37.5% vs.9.5%, p = 0.021), subjects with severe COVID-19 were more obese compared to those with non-severe disease (89.5% vs.59.6%, p = 0.021), while, the presence of obesity in MAFLD patients was associated with a ~6-fold increased risk of severe COVID-19 illness, and this association remained significant even after adjusting for age, sex, smoking, diabetes, hypertension and dyslipidemia, suggesting that, in the context of MAFLD, obesity represents an important risk factor for COVID-19 severity. Obesity-driven chronic inflammation and impaired fibrinolysis contribute to increase the risk of developing thrombosis, which currently seems to be one of the mechanisms potentially involved in worsening lung damage and in death, this justifies the use of heparin for both prophylactic and therapeutic purposes in different protocols used in patients with COVID-19 [[17]www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspectedDate accessed: April 3, 2020Google Scholar]. In fact, using pulmonary and cutaneous biopsy and autopsy samples from individuals with severe COVID-19 it has been documented that some SARS-CoV-2-infected patients who became critically ill suffered a generalized thrombotic microvascular injury [[18]Magro C. Mulvey J. Berlin D. Nuovo G. Salvatore S. Harpe J. et al.Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases.Transl Res. April 2020; https://doi.org/10.1016/j.trsl.2020.04.007Abstract Full Text Full Text PDF PubMed Scopus (1388) Google Scholar]. Another common finding in obesity is vitamin D deficiency that has been reported to increase the risk of systemic infections and to impair immune response [[19]Bouillon R. Marcocci C. Carmeliet G. et al.Skeletal and extraskeletal actions of vitamin D: current evidence and outstanding questions.Endocr Rev. 2019; 40: 1109-1151https://doi.org/10.1210/er.2018-00126Crossref PubMed Scopus (394) Google Scholar]. Conversely vitamin D supplementation can prevent respiratory infections through several immunoregulatory functions including the decreased production of pro-inflammatory cytokines by the innate immune system, therefore reducing the risk of a cytokine storm leading to pneumonia [[20]Martineau A.R. Jolliffe D.A. Hooper R.L. et al.Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data.BMJ. 2017; 356: i6583https://doi.org/10.3310/hta23020Crossref PubMed Scopus (171) Google Scholar]. Interestingly, epidemiological data report that Italy is one of the Countries with the highest prevalence of hypovitaminosis D in Europe, with a very high prevalence in subjects with obesity and elderly women with diabetes [[21]Isaia G. Giorgino R. Rini G.B. et al.Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors.Osteoporos Int. 2003; 14: 577-582https://doi.org/10.1007/s00198-003-1390-7Crossref PubMed Scopus (240) Google Scholar,[22]Formenti A.M. Tecilazich F. Frara S. et al.Body mass index predicts resistance to active vitamin D in patients with hypoparathyroidism.Endocrine. 2019; 66: 699-700https://doi.org/10.1007/s12020-019-02105-6Crossref PubMed Scopus (17) Google Scholar]. Therefore, based on the previous considerations it could be hypothesized that vitamin D deficiency could potentially take part to the link between obesity and increased susceptibility to complications and mortality due to COVID-19 [[23]Grant W.B. Lahore H. McDonnell S.L. et al.Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths.Nutrients. 2020; 12 (pii: E988)https://doi.org/10.3390/nu12040988Crossref PubMed Scopus (1087) Google Scholar]. Gut dysbiosis is another important factor potentially involved in the increased risk of developing severe forms of COVID-19 in obesity. As well-known obesity per se is associated to a blunted composition of gut microbiome that in turn is paramount for the regulation of the host's immune system and for the protection from infection. Moreover, gut microbiome also has a role in attenuating the damage consequent to infection. In fact some protocols for the treatment of COVID-19 include the use of probiotics to maintain the balance of intestinal microecology and therefore indirectly strengthen immune system [[24]Ying-Hui J. Lin C. Zhen-Shun C. et al.A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia.Mil Med Res. 2020; 7: 4https://doi.org/10.1186/s40779-020-0233-6Crossref PubMed Scopus (1339) Google Scholar,[25]Torres-Fuentes C. Schellekens H. Dinan T.G. et al.The microbiota-gut-brain axis in obesity.Lancet Gastroenterol Hepatol. 2017; 2: 747-756https://doi.org/10.1016/S2468-1253(17)30147-4Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar]. Finally, subjects with obesity have also mechanical issues related to excessive weight that make difficult an early diagnosis with pulmonary ultrasound and thus leading to a diagnosis of COVID-19 in the advanced stage which is most associated to highest mortality. The lack of medical or intensive care units not designed to accommodate patients with severe obesity, the difficulties of intubation and insertion of catheters related to excess of weight may lead to a slowdown in therapeutic steps, worsening prognosis in patients with obesity and COVID-19. Furthermore, in no infected subjects with obesity currently subjected to strict measures to contain the pandemic, close monitoring including the use of telemedicine is required, because of less physical activities, unhealthy food consumption (processed and long-life foods, caloric foods), reduction in healthier fresh options (fruits and vegetables), stress anxiety and sleep deprivation under the pressure of social distancing [[26]Rebelos E. Moriconi D. Virdis A. Taddei S. Foschi D. Nannipieri M. Importance of metabolic health in the era of COVID-19.Metabolism. 2020 Apr 22; ([Epub ahead of print] PubMed PMID: 32333939): 154247https://doi.org/10.1016/j.metabol.2020.154247Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar,[27]Muscogiuri G. Barrea L. Savastano S. Colao A. Nutritional recommendations for CoVID-19 quarantine.Eur J Clin Nutr. 2020 Apr 14; https://doi.org/10.1038/s41430-020-0635-2Crossref PubMed Scopus (259) Google Scholar]. Taken all together, subjects with obesity are high-risk and complicated group of patients to treat for COVID19, with an increased requirement of hospitalization. Subjects with obesity need intensive attention to reduce the risk of fatalities. Thus, it is paramount that these subjects avoid infections following the general prevention advices given by the authorities in order to reduce the spread of the virus. This manuscript has some limitations related to the lack of scientific evidence produced so far due to the recent onset and rapid spread of the pandemic, however it represents an accessible summary of the epidemiological evidence and possible pathophysiological mechanisms regarding obesity and COVID-19. Retrospective studies on a larger sample of the population will be needed, as well as autopsy studies and especially randomized clinical trials with the aim of understanding which individuals are most at risk of becoming infected or developing complications, what are the causal mechanisms on which it is possible to intervene with prophylactic and therapeutic measures and what the long-term consequences will be on the health of patients with obesity. Giovanna Muscogiuri: Conceptualization, data curation, writing - review & editing. Gabriella Pugliese: Conceptualization, data curation. Luigi Barrea: Conceptualization. Silvia Savastano: Writing - review & editing. Annamaria Colao: Writing - review & editing.

The primary aim of this study was to evaluate the temporal correlation between Wikitrends and conventional surveillance data generated for measles infection reported by bulletin of Istituto Superiore di Sanità (ISS). The reported cases of measles were selected from July 2015 to October 2018. Wikipedia Trends was used to assess how many times a specific page was read by users, data were extracted as daily data and aggregated on a weekly and monthly basis. The following data were extracted: number of views by users from 1 July 2015 to 31 October 2018 of the Morbillo, Vaccinazione del Morbillo, Vaccinazione MPR and Macchie di Koplik pages (Measles, Measles Vaccination, MPR Vaccination and Koplik's spots in English). Cross-correlation results were obtained as product-moment correlations between the two time series. Regarding the database with monthly data, temporal correlation was observed between the bulletin of ISS and Wikipedia search trends: the strongest correlation was at a lag of 0 for Measles (r=0.9164), Measles Vaccination (r=0.8622), MPR Vaccination (r=0.7852) and Koplik's spots (r=0.8217). Regarding the database with weekly data, both moderate and strong correlation was observed. A possible future application for programming and management interventions of Public Health is proposed.

The primary aim of this study is to evaluate the temporal correlation between Google Trends and the data on measles infection arising from the conventional surveillance system, reported by the Istituto Superiore di Sanità's (ISS) bulletin. Moreover, this study is also aimed at forecasting the trends of the reported infectious diseases cases over time. The reported cases of measles were selected from January 2013 until October 2018. The data on Internet searches have been obtained from Google Trends; the research data referred to the first 48 weeks of year 2017 have been aggregated on a weekly basis. The search volume provided by Google Trends has a relative nature and is calculated as a percentage of query related to a specific term in connection with a determined place and time-frame. The statistical analyses have been performed by using the Spearman's rank correlation coefficient (rho). The statistical significance level for such analyses has been fixed in 0.05. We have observed a strong correlation at a lag of 0 to -4 weeks (rho > 0.70) with the cases reported by ISS with the strongest correlation at a lag of -3 weeks (rho > 0.80 both for measles than for the symptoms of the measles). The database containing monthly data has shown a moderate correlation at a lag of -1 to +1 months and a strongest correlation at a lag of -1 (rho = 0.6152 for measles and rho = 0.5039 for symptoms of the measles). The surveillance systems based on Google Trends have a potential role in public health in order to provide near real-time indicators of the spread of infectious diseases. Therefore the huge potential of this approach could be used in the immediate future as a support of the traditional surveillance systems.

Both the World Health Organization (WHO) with its 2015 "Climate and Health Country Profile Project" and the Istituto Superiore di Sanità (ISS) with its 2018 "Health and Climate Change", agree on the emergency generated by the climate change and concerning health problems. The mitigation strategy suggested by the Intergovernmental Panel On Climate Change (IPCC) against greenhouse gas emissions and their effects on climate change, has not yet yielded the desired results. It is therefore necessary to focus on adaptation strategies, to immediately counter the effects of climate change (CC) on most vulnerable people and environments, by increasing their resilience through local interventions and targeted resilience actions. Coordinated resilience actions are necessary to combat the effects of CC especially in urban areas. Useful tools to manage and optimize resilience actions are artificial neural networks (ANN) in complex and dynamic domains as cities are. The case of ANN applied to a city is presented as an example to increase the climate resilience of health local systems. In the current state of knowledge, ANN prove to be the most advanced and global solution to coordinate and manage a set of resilience actions in urban areas.

Istituto Superiore Di Sanità Research Articles

Articles published on Istituto Superiore Di Sanità

Technical and health governance aspects of the external quality assessment system for classical and new psychoactive substances analysis testing in blood

Hepatitis C virus screening in Piemonte: an effective strategy to eliminate HCV chronic infections

Capacity building to boost information and communication skills inside an institute of research

The Rare Book Collection of the Library of the Italian National Institute of Health: from the past to the present

The role of analytical pharmacotoxicology in adressing the main functions of the National Early Warning System on NPS

Non-alcoholic fatty liver disease in adults 2021: A clinical practice guideline of the Italian Association for the Study of the Liver (AISF), the Italian Society of Diabetology (SID) and the Italian Society of Obesity (SIO).

Technologies to Support Frailty, Disability, and Rare Diseases: Towards a Monitoring Experience during the COVID-19 Pandemic Emergency.

Comparison of hospitalizations and deaths from COVID-19 2021 versus 2020 in Italy: surprises and implications.

An Italy-China Collaboration for Promoting Public Mental Health Recommendations During the COVID-19 Pandemic.

Obesity as a risk factor for hospitalization in COronaVirus Disease-19 (COVID-19) patients: Analysis of the Tuscany regional database

Rapid scientific update response to public health professions during Phase I of COVID-19 pandemic

Profiling biopsychosocial health of cancer-diagnosed elderly in Italy by Passi d’Argento, 2016-2017

How to Obtain an Orthodontic Virtual Patient through Superimposition of Three-Dimensional Data: A Systematic Review

Evaluation and Management of Patients with Methomyl Poisoning – A Case Report

Parallel epidemics, or nearly so: Certainties and uncertainties about SARS-CoV-2 in Italy

The Italian External Quality Assessment Program for Cystic Fibrosis Sweat Chloride Test: Does Active Participation Improve the Quality?

Commentary: Obesity: The “Achilles heel” for COVID-19?

Predicting disease outbreaks: evaluating measles infection with Wikipedia Trends.

Digital epidemiology: assessment of measles infection through Google Trends mechanism in Italy.

Resilience actions to counteract the effects of climate change and health emergencies in cities: the role of artificial neural networks.

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